Pharmaceutical composition, method for producing pharmaceutical composition, dissolution improving agent, and method for improving dissolution

Abstract

Provided is a novel pharmaceutical composition comprising nintedanib as an active ingredient, wherein the active ingredient is favorably eluted under weakly acidic conditions.SOLUTION: The pharmaceutical composition of the present invention comprises methyl (3Z) - 3 - [({4 - [N-methyl-2 - (4-methylpiperazin-1-yl) acetamido] phenyl} amino) (phenyl) methylidene] - 2-oxo-2, 3-dihydro - 1H - indole-6-carboxylate, or pharmaceutically acceptable salts thereof, as active ingredient (1), and a lipophilic co-surfactant (2) and / or a halide of an alkaline or alkaline earth metal (3).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising, as an active ingredient, methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, a method for producing the pharmaceutical composition, an agent for improving the dissolution of a solid active ingredient such as the active ingredient, and a method for improving the dissolution of the solid active ingredient. [Background technology]

[0002] Methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "nintedanib") is a compound that exhibits pharmacological effects in the treatment of cancer diseases, immune diseases, symptoms associated with immune diseases, or fibrosis.

[0003] Nintedanib exhibits a high dissolution rate under strongly acidic conditions (e.g., pH less than 1.2), but its dissolution rate is known to decrease as the acidity decreases (e.g., pH 1.2 or higher). However, because pharmaceutical compositions containing nintedanib as an active ingredient are usually taken orally after meals, it is necessary to devise a formulation that exhibits a good dissolution rate under weakly acidic conditions in the stomach (e.g., pH 1.2 to 6.0).

[0004] Patent Document 1 discloses that adding a specific amount of lecithin to nintedanib improves the dissolution rate of nintedanib at pH 1. It also discloses that adding the surfactant Tween 80 can suppress a decrease in dissolution rate even at pH 3. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2014-98045 Summary of the Invention [Problem to be solved by the invention]

[0006] However, Patent Document 1 does not disclose that the dissolution rate under weakly acidic conditions can be improved by adding a lipophilic co-surfactant (2) and / or an alkali metal or alkaline earth metal halide (3) to nintedanib.

[0007] Therefore, an object of the present invention is to provide a novel pharmaceutical composition containing nintedanib as an active ingredient, in which the active ingredient is well dissolved under weakly acidic conditions. Another object of the present invention is to provide a method for producing the pharmaceutical composition. Another object of the present invention is to provide a novel dissolution-improving agent for nintedanib. Another object of the present invention is to provide a method for improving the dissolution rate of nintedanib. Another object of the present invention is to provide an agent for improving the dissolution rate of a solid active ingredient in a pharmaceutical composition containing the active ingredient. Another object of the present invention is to provide a method for improving the dissolution rate of a solid active ingredient in a pharmaceutical composition containing the active ingredient. [Means for solving the problem]

[0008] Nintedanib (1) is a hydrophobic compound. It is also easily hydrolyzed and is typically used in capsule-shell formulations. However, nintedanib (1) tends to aggregate when placed inside a capsule shell. Therefore, it is difficult to dissolve in water, especially in the weakly acidic stomach, and the desired dissolution rate cannot be achieved.

[0009] As a result of extensive research into solving the above problems, the present inventors have discovered the following. 1. Adding a lipophilic co-surfactant (2) to nintedanib (1) makes nintedanib (1) more compatible with water, improving the dissolution rate of nintedanib (1). 2. When alkali metal or alkaline earth metal halide (3) is added to nintedanib (1), the alkali metal or alkaline earth metal halide (3) exists as a solid component and penetrates between the particles of nintedanib (1), suppressing the aggregation of nintedanib (1) in the pharmaceutical composition, thereby improving the dissolution rate of nintedanib (1) in water. 3. When alkali metal or alkaline earth metal halide (3) is added to nintedanib (1), the alkali metal or alkaline earth metal halide (3) is easily soluble in water, which makes nintedanib (1) more compatible with water and improves its dissolution rate in water. The present invention was completed based on these findings.

[0010] That is, the present invention relates to a method for treating a rheumatoid arthritis (HVA) comprising administering to a patient a therapeutically effective amount of methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, which is an active ingredient (1); a lipophilic co-surfactant (2); The present invention provides a pharmaceutical composition comprising:

[0011] The present invention also provides a lipophilic co-surfactant (2) represented by the following formula (2a): HO-(R 1 -O) n -H (2a) (In the formula, R 1 represents an alkylene group which may have a substituent, and n represents an integer of 1 or more. The pharmaceutical composition is provided with a (poly)alkylene polyol represented by the following formula:

[0012] The present invention also provides the pharmaceutical composition, wherein the lipophilic cosurfactant (2) has a number average molecular weight of 100-1,000.

[0013] The present invention also provides a lipophilic cosurfactant (2) having a kinematic viscosity at 98.9°C of 1 to 15 mmHg. 2 / s of the pharmaceutical composition.

[0014] The present invention also provides the pharmaceutical composition, wherein the lipophilic co-surfactant (2) is polyethylene glycol.

[0015] The present invention also provides the pharmaceutical composition, wherein the content of the lipophilic co-surfactant (2) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1).

[0016] The present invention also provides the pharmaceutical composition, further comprising an alkali metal or alkaline earth metal halide (3).

[0017] The present invention also provides the pharmaceutical composition, wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide.

[0018] The present invention also provides the pharmaceutical composition, wherein the weight ratio of the lipophilic co-surfactant (2) to the alkali metal or alkaline earth metal halide (3) (former / latter) is 40 / 60 to 85 / 15.

[0019] The present invention also provides the pharmaceutical composition, wherein the content of the alkali metal or alkaline earth metal halide (3) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1).

[0020] The present invention also provides the pharmaceutical composition, further comprising at least one surfactant (4) selected from polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, and (poly)glycerin fatty acid ester.

[0021] The present invention also provides the pharmaceutical composition, which further comprises an oily base (5).

[0022] The present invention also provides the pharmaceutical composition, wherein the content of the oily base (5) is 0.5 to 2 parts by weight per 1 part by weight of the active ingredient (1).

[0023] The present invention also provides the pharmaceutical composition, wherein the dosage form is a capsule or tablet.

[0024] The present invention also provides a method for producing a pharmaceutical composition, which comprises mixing the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with a lipophilic co-surfactant (2) to obtain the pharmaceutical composition.

[0025] The present invention also provides a dissolution improver for improving the dissolution rate of the active ingredient (1) in a pharmaceutical composition comprising methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, the agent comprising: A dissolution improver containing a lipophilic cosurfactant (2) is provided.

[0026] The present invention also provides a method for improving the dissolution of the active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof (1), by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the active ingredient (1).

[0027] The present invention also provides a dissolution improver for improving the dissolution rate of a solid active ingredient (1') from a pharmaceutical composition containing the active ingredient (1'), comprising: A dissolution improver containing a lipophilic cosurfactant (2) is provided.

[0028] The present invention also provides a method for improving the dissolution of a solid active ingredient (1') by incorporating a lipophilic co-surfactant (2) into a pharmaceutical composition containing the active ingredient (1').

[0029] The present invention also relates to a method for treating a rheumatoid arthritis (HPA) disease, comprising administering to a patient a therapeutically effective amount of methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, which is an active ingredient (1); an alkali metal or alkaline earth metal halide (3); The present invention provides a pharmaceutical composition comprising:

[0030] The present invention also provides the pharmaceutical composition, wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide.

[0031] The present invention also provides a method for producing a pharmaceutical composition, which comprises mixing the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with an alkali metal or alkaline earth metal halide (3), to obtain the pharmaceutical composition.

[0032] The present invention also provides a dissolution improver for improving the dissolution rate of the active ingredient (1) in a pharmaceutical composition comprising methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, the agent comprising: The present invention provides a dissolution improver containing an alkali metal or alkaline earth metal halide (3).

[0033] The present invention also provides a method for improving the dissolution rate of the active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, by incorporating an alkali metal or alkaline earth metal halide (3) into a pharmaceutical composition containing the active ingredient (1).

[0034] The present invention also provides a dissolution improver for improving the dissolution rate of a solid active ingredient (1') from a pharmaceutical composition containing the active ingredient (1'), the dissolution improver comprising an alkali metal or alkaline earth metal halide (3).

[0035] The present invention also provides a method for improving the dissolution rate by adding an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing a solid active ingredient (1'). [Effects of the Invention]

[0036] The pharmaceutical composition of the present invention contains nintedanib (1) as an active ingredient, as well as a lipophilic cosurfactant (2) and / or an alkali metal or alkaline earth metal halide (3), which inhibits aggregation of nintedanib (1) and / or improves the affinity of nintedanib (1) to water, resulting in an excellent dissolution rate in water (even in water with low acidity). In particular, when the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3), the alkali metal or alkaline earth metal halide (3) exists in a solid state even in summer, penetrates into the gaps between the particles of nintedanib (1), and physically suppresses the aggregation of nintedanib (1). Therefore, even if the pharmaceutical composition is not stored in a cold place, the decrease in dissolution rate over time can be suppressed, and handling is easy. Furthermore, when the pharmaceutical composition contains a surfactant (4) together with nintedanib (1) as an active ingredient, the surfactant (4) increases the dispersibility of nintedanib (1) and suppresses aggregation, so that nintedanib (1) can exhibit an excellent dissolution rate even under weakly acidic conditions. [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 is a graph showing the change in dissolution rate over time in an atmosphere of pH 3 for the capsules obtained in Examples 1 to 7. [Figure 2] FIG. 1 shows the change in dissolution rate over time in a pH 3 atmosphere for the capsules obtained in Example 8. [Figure 3] FIG. 1 shows the change in dissolution rate over time of the capsules obtained in Example 8 in an atmosphere of pH 1.2. DETAILED DESCRIPTION OF THE INVENTION

[0038] [Pharmaceutical composition] The pharmaceutical composition of the present invention comprises nintedanib (1) as an active ingredient, and is composed of a composition containing nintedanib (1) together with a lipophilic co-surfactant (2) and / or an alkali metal or alkaline earth metal halide (3).

[0039] The compositions constituting the pharmaceutical composition include the following aspects. 1. An embodiment comprising nintedanib (1) as an active ingredient, a lipophilic co-surfactant (2), and an alkali metal or alkaline earth metal halide (3). 2. An embodiment containing nintedanib (1) as an active ingredient and a lipophilic co-surfactant (2), and not containing an alkali metal or alkaline earth metal halide (3). 3. An embodiment containing nintedanib (1) as an active ingredient and an alkali metal or alkaline earth metal halide (3), and not containing a lipophilic co-surfactant (2).

[0040] The pharmaceutical composition may further contain other ingredients, such as surfactants (4) and oily bases (5).

[0041] (Nintedanib (1)) Nintedanib (1) is a compound represented by the following formula (1a) (i.e., methyl(3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate), or a pharmaceutically acceptable salt of the compound represented by the following formula (1a). [ka]

[0042] Examples of pharmaceutically acceptable salts of the compound represented by formula (1a) include inorganic acid salts (e.g., hydrochloride, sulfate), organic acid salts (e.g., benzenesulfonate, toluenesulfonate, methanesulfonate, ethanesulfonate), and the like.

[0043] Among nintedanib (1), nintedanib ethanesulfonate is a compound with a melting point of 305±5°C and is a solid at room temperature.

[0044] Furthermore, nintedanib (1) is a hydrophobic compound and therefore does not readily dissolve in water. However, in the present invention, the pharmaceutical composition contains, together with nintedanib (1), a lipophilic co-surfactant (2) and / or an alkali metal or alkaline earth metal halide (3), which improves the wettability of nintedanib (1), making it more readily compatible with water and increasing the dissolution rate.

[0045] Furthermore, nintedanib (1) is prone to aggregation, but when the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) in a solid state together with nintedanib (1), the solid alkali metal or alkaline earth metal halide (3) penetrates between the particles of nintedanib (1) to suppress aggregation and highly disperse the nintedanib (1). This suppresses aggregation of nintedanib (1), making it more compatible with water and improving the dissolution rate.

[0046] From the viewpoint of increasing the dissolution rate under weakly acidic conditions, nintedanib (1) is preferably contained in the pharmaceutical composition in a highly dispersed state, and the particle size (D50) of nintedanib (1) in the pharmaceutical composition is, for example, 50 μm or less (e.g., 1 to 50 μm), preferably 30 μm or less, particularly preferably 20 μm or less, most preferably 15 μm or less, and particularly preferably 13 μm or less. The lower limit of the particle size (D50) is, for example, 5 μm or 10 μm.

[0047] The content of nintedanib (1) is, for example, 5 to 60% by weight of the total amount (100% by weight) of the pharmaceutical composition. The lower limit of the content is preferably 10% by weight, more preferably 20% by weight, particularly preferably 30% by weight, and most preferably 35% by weight. The upper limit of the content is preferably 55% by weight, and most preferably 50% by weight.

[0048] The content of nintedanib (1) per pharmaceutical composition (e.g., per capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 5 to 1000 mg, preferably 25 to 300 mg.

[0049] (Lipophilic co-surfactant (2)) Examples of the lipophilic co-surfactant (2) (hereinafter sometimes simply referred to as "co-surfactant (2)") include (poly)alkylene polyols represented by the following formula (2a): HO-(R 1 -O) n -H (2a) (In the formula, R 1 represents an alkylene group which may have a substituent, and n represents an integer of 1 or more.

[0050] (Poly)alkylene polyols include alkylene polyols and polyalkylene polyols.

[0051] R 1 Examples of the alkylene group in the formula (I) include linear or branched alkylene groups having 1 to 5 carbon atoms, such as methylene, methylmethylene, dimethylmethylene, ethylene, propylene, and trimethylene. Of these, alkylene groups having 1 to 3 carbon atoms are preferred, alkylene groups having 2 or 3 carbon atoms are particularly preferred, and ethylene groups are particularly preferred.

[0052] Examples of the substituent that the alkylene group may have include a hydroxyl group, C 1-5 Alkoxy group, C 1-5 Examples include an acyl group.

[0053] The n is an integer of 1 or more, for example, an integer of 1 to 20. From the viewpoint of improving the dissolution rate of nintedanib (1), the upper limit of n is preferably 18, particularly preferably 15, most preferably 12, and particularly preferably 10. From the viewpoint of improving the dissolution rate of nintedanib (1), the lower limit of n is preferably 2, particularly preferably 3, most preferably 4, and particularly preferably 5.

[0054] When n is an integer of 2 or more, n R 1 may be the same or different.

[0055] In addition, the n is an integer of 2 or more, and n R 1 When R 1 The polymerization method of the repeating unit represented by (R) is not particularly limited, and may be, for example, block polymerization, graft copolymerization, random polymerization, etc. That is, the (poly)alkylene polyol is a polyol in which n is an integer of 2 or more, and n R 1 When is two or more different groups, the copolymer may be any of a block copolymer, a graft copolymer, and a random copolymer.

[0056] The number average molecular weight of the cosurfactant (2) is, for example, 100 to 1000. From the viewpoint of improving the dissolution rate of nintedanib (1), the upper limit of the molecular weight is preferably 800, particularly preferably 700, most preferably 600, and particularly preferably 500. From the viewpoint of improving the dissolution rate of nintedanib (1), the lower limit of the molecular weight is preferably 250, particularly preferably 300, and most preferably 350.

[0057] The kinematic viscosity of the cosurfactant (2) at 98.9°C (preferably at 98.9°C under normal pressure) is, for example, 1 to 15 mm 2 The lower limit of the kinematic viscosity is preferably 3 mm / s from the viewpoint of improving the dissolution rate of nintedanib (1). 2 / s, particularly preferably 5 mm 2 / s, most preferably 7 mm 2 The upper limit of the kinematic viscosity is preferably 12 mm / s from the viewpoint of improving the dissolution rate of nintedanib (1). 2 / s, particularly preferably 10 mm 2 / s, most preferably 8 mm 2 / s.

[0058] Specific examples of the co-surfactant (2) include (poly)ethylene glycol, (poly)propylene glycol, (poly)butylene glycol, (poly)ethylenepolypropylene glycol, and (poly)ethylenepolybutylene glycol.

[0059] Of these, (poly)ethylene glycol is preferred as the co-surfactant (2), and polyethylene glycol is particularly preferred.

[0060] The content of the cosurfactant (2) is, for example, 3 to 30% by weight of the total amount (100% by weight) of the pharmaceutical composition. The lower limit of the content is preferably 5% by weight, more preferably 7% by weight, and particularly preferably 8% by weight. The upper limit of the content is preferably 25% by weight, particularly preferably 20% by weight, most preferably 15% by weight, and particularly preferably 12% by weight.

[0061] The content of the co-surfactant (2) is, for example, 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1). The lower limit of the content is preferably 5 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, and most preferably 20 parts by weight. The upper limit of the content is preferably 40 parts by weight, particularly preferably 35 parts by weight, most preferably 30 parts by weight, and particularly preferably 28 parts by weight.

[0062] The content of the cosurfactant (2) per pharmaceutical composition (e.g., per capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 20 to 60 mg, preferably 25 to 55 mg.

[0063] (Alkali metal or alkaline earth metal halides (3)) The alkali metal or alkaline earth metal halide (3) exists in a solid state in the pharmaceutical composition, penetrates between particles of nintedanib (1), and exerts the effect of inhibiting aggregation.

[0064] Examples of the alkali metal or alkaline earth metal halide (3) include chlorides such as sodium chloride, potassium chloride, calcium chloride, and barium chloride; iodides such as sodium iodide, potassium iodide, calcium iodide, and barium iodide; and bromides such as sodium bromide.

[0065] As the alkali metal or alkaline earth metal halide (3), an alkali metal halide is preferred, an alkali metal chloride or iodide is more preferred, and at least one compound selected from sodium chloride, potassium chloride, and sodium iodide is particularly preferred, with sodium chloride being most preferred, as it has an excellent effect of inhibiting the aggregation of nintedanib (1).

[0066] The content of the alkali metal or alkaline earth metal halide (3) is, for example, 1 to 50% by weight of the total amount (100% by weight) of the pharmaceutical composition. The lower limit of the content is preferably 2% by weight, more preferably 5% by weight, even more preferably 7% by weight, even more preferably 7.5% by weight, even more preferably 8% by weight, even more preferably 9% by weight, and particularly preferably 10% by weight. The upper limit of the content is preferably 25% by weight, and particularly preferably 20% by weight.

[0067] The content of the alkali metal or alkaline earth metal halide (3) is, for example, 1 to 50 parts by weight per 100 parts by weight of the active ingredient (1). The lower limit of the content is preferably 2 parts by weight, more preferably 5 parts by weight, even more preferably 7 parts by weight, even more preferably 10 parts by weight, even more preferably 15 parts by weight, particularly preferably 20 parts by weight, and most preferably 25 parts by weight. The upper limit of the content is preferably 40 parts by weight, particularly preferably 35 parts by weight, and most preferably 30 parts by weight.

[0068] The content of the alkali metal or alkaline earth metal halide (3) per pharmaceutical composition (e.g., per capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 5 to 60 mg, preferably 25 to 55 mg.

[0069] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) together with a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) is, for example, 1 to 50% by weight of the total amount (100% by weight) of the pharmaceutical composition. The lower limit of the content is preferably 2% by weight, more preferably 5% by weight, even more preferably 7% by weight, even more preferably 7.5% by weight, even more preferably 8% by weight, even more preferably 9% by weight, and particularly preferably 10% by weight. The upper limit of the content is preferably 25% by weight, particularly preferably 20% by weight, most preferably 15% by weight, and particularly preferably 12% by weight.

[0070] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) together with a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) is, for example, 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1). The lower limit of the content is preferably 5 parts by weight, more preferably 10 parts by weight, even more preferably 15 parts by weight, particularly preferably 20 parts by weight, most preferably 25 parts by weight, and particularly preferably 27 parts by weight. The upper limit of the content is preferably 40 parts by weight, particularly preferably 35 parts by weight, and most preferably 30 parts by weight.

[0071] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) together with a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) per pharmaceutical composition (e.g., per capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 5 to 60 mg, preferably 25 to 55 mg, particularly preferably 30 to 55 mg, and most preferably 35 to 55 mg.

[0072] When the pharmaceutical composition contains a lipophilic cosurfactant (2) and an alkali metal or alkaline earth metal halide (3), the weight ratio of the lipophilic cosurfactant (2) to the alkali metal or alkaline earth metal halide (3) (former / latter) is, for example, 40 / 60 to 85 / 15. The lower limit of this weight ratio is preferably 45 / 55. The upper limit of this weight ratio is preferably 70 / 30, particularly preferably 60 / 40, and most preferably 55 / 45.

[0073] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) but does not contain a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) is, for example, 1 to 50 wt% of the total amount of the pharmaceutical composition (100 wt%). The lower limit of the content is preferably 2 wt%, more preferably 5 wt%, even more preferably 7 wt%, even more preferably 7.5 wt%, even more preferably 8 wt%, even more preferably 9 wt%, particularly preferably 10 wt%, and most preferably 13 wt%. The upper limit of the content is preferably 35 wt%, particularly preferably 30 wt%, most preferably 25 wt%, and particularly preferably 20 wt%.

[0074] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) but does not contain a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) is, for example, 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1). The lower limit of the content is preferably 5 parts by weight, more preferably 10 parts by weight, even more preferably 15 parts by weight, particularly preferably 20 parts by weight, and most preferably 25 parts by weight. The upper limit of the content is preferably 40 parts by weight, particularly preferably 35 parts by weight, and most preferably 30 parts by weight.

[0075] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) but does not contain a lipophilic cosurfactant (2), the content of the alkali metal or alkaline earth metal halide (3) per pharmaceutical composition (e.g., per capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 5 to 60 mg, preferably 25 to 55 mg, particularly preferably 30 to 55 mg, most preferably 40 to 55 mg, and particularly preferably 45 to 50 mg.

[0076] (Surfactant (4)) The surfactant (4) acts to uniformly disperse nintedanib (1) in the pharmaceutical composition and further improve the dissolution rate.

[0077] The surfactant (4) includes cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants, which may be used alone or in combination of two or more.

[0078] In the present invention, it is preferable to use a nonionic surfactant because it has an excellent effect of improving the dispersibility of nintedanib (1).

[0079] Nonionic surfactants include ester-type nonionic surfactants, ether-type nonionic surfactants, and ether-ester-type nonionic surfactants.

[0080] Examples of the ester-type nonionic surfactants include polyoxyethylene hydrogenated castor oil; sucrose fatty acid esters; (poly)glycerin fatty acid esters; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene (3) glyceryl monoisostearate, polyoxyethylene (6) glyceryl monoisostearate, polyoxyethylene (8) glyceryl monoisostearate, polyoxyethylene (10) glyceryl monoisostearate, polyoxyethylene (15) glyceryl monoisostearate, polyoxyethylene (20) glyceryl monoisostearate, polyoxyethylene (30) glyceryl monoisostearate, polyoxyethylene (10) glyceryl triisostearate, polyoxyethylene (20) glyceryl triisostearate, polyoxyethylene (30) glyceryl triisostearate, and polyoxyethylene (40) glyceryl triisostearate; sorbitan monooleate, and monostearin. Examples of suitable sorbitan fatty acid esters include sorbitan monolaurate, polyoxyethylene (6) sorbitan monolaurate, polyoxyethylene (20) sorbitan monostearate, and polyoxyethylene (20) sorbitan monooleate; polyoxyethylene trimethylolpropane fatty acid esters include polyoxyethylene (8) trimethylolpropane trimyristate, polyoxyethylene (20) trimethylolpropane trimyristate, and polyoxyethylene (30) trimethylolpropane trimyristate; polyoxyethylene sorbitol fatty acid esters include polyoxyethylene (30) sorbitol tetraoleate and polyoxyethylene (40) sorbitol tetraoleate; and polyoxyethylene fatty acid esters include polyoxyethylene (6) diisostearate and polyoxyethylene (12) diisostearate. These may be used alone or in combination of two or more.

[0081] Examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene (5-100) hydrogenated castor oils (the number in parentheses indicates the degree of polymerization of the oxyethylene group, preferably a number from 10 to 100, particularly preferably a number from 30 to 100), such as polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (7) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. These may be used alone or in combination of two or more.

[0082] Examples of the sucrose fatty acid ester include sucrose C esters such as sucrose erucate, sucrose stearate, sucrose palmitate, sucrose myristate, sucrose oleate, sucrose laurate, and sucrose behenate. 10-25 Saturated or unsaturated fatty acid esters can be used alone or in combination of two or more.

[0083] The (poly)glycerin fatty acid ester may be, for example, a (poly)glycerin having a degree of polymerization of glycerin units of 1 to 10, such as diglyceryl monostearate, polyglyceryl-4 pentaoleate, or polyglyceryl-6 pentaoleate, and a (poly)glycerin fatty acid ester of C 10-25 Examples include esters with 1 to 10 moles (preferably 1 to 5 moles) of saturated or unsaturated fatty acids. These can be used alone or in combination of two or more.

[0084] Examples of the ether-type nonionic surfactant include polyoxyethylene alkylphenyl ethers such as polyoxyethylene octylphenyl ether and polyoxyethylene nonylphenyl ether, and polyoxyethylene alkyl ethers, which may be used alone or in combination of two or more.

[0085] Examples of the ether-ester type nonionic surfactants include polyoxyethylene (5) cetyl ether stearate, polyoxyethylene (10) cetyl ether stearate, etc. These may be used alone or in combination of two or more.

[0086] As the surfactant (4), at least one compound selected from the surfactants exemplified above is preferred, at least one compound selected from polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, and (poly)glycerin fatty acid ester is particularly preferred, and polyoxyethylene hydrogenated castor oil is most preferred.

[0087] In the total amount (100% by weight) of surfactant (4) contained in the pharmaceutical composition, the content of at least one compound selected from polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, and (poly)glycerin fatty acid ester (the total amount when two or more types are contained) (particularly preferably the content of polyoxyethylene hydrogenated castor oil) is preferably 50% by weight or more, more preferably 60% by weight or more, more preferably 70% by weight or more, even more preferably 80% by weight or more, particularly preferably 90% by weight or more, most preferably 95% by weight or more, and particularly preferably 99% by weight or more. The upper limit of the content is 100% by weight.

[0088] The content of surfactant (4) (total amount when two or more types are contained) is, for example, 0.1 to 10 wt% of the total amount of the pharmaceutical composition (100 wt%). The lower limit of the content is preferably 1 wt%, more preferably 3 wt%, even more preferably 4 wt%, particularly preferably 4.5 wt%, most preferably 4.7 wt%, and particularly preferably 4.8 wt%. The upper limit of the content is preferably 8 wt%, more preferably 7 wt%, even more preferably 6 wt%, particularly preferably 5.5 wt%, and most preferably 5 wt%.

[0089] The content of surfactant (4) is, for example, 0.1 to 20 parts by weight per 100 parts by weight of nintedanib (1). The lower limit of the content is preferably 1% by weight, more preferably 3% by weight, even more preferably 5% by weight, even more preferably 8% by weight, particularly preferably 10% by weight, most preferably 11% by weight, and particularly preferably 12% by weight. The upper limit of the content is preferably 17% by weight, more preferably 16% by weight, particularly preferably 15% by weight, most preferably 14% by weight, and particularly preferably 13.5% by weight.

[0090] When the pharmaceutical composition contains a lipophilic cosurfactant (2) and a surfactant (4), the content of surfactant (4) is, for example, 0.1 to 10 parts by weight per part by weight of the lipophilic cosurfactant (2). The lower limit of the content of surfactant (4) is preferably 0.2 parts by weight, particularly preferably 0.3 parts by weight, and most preferably 0.4 parts by weight. The upper limit of the content of surfactant (4) is preferably 5 parts by weight, more preferably 3 parts by weight, more preferably 2 parts by weight, even more preferably 1 part by weight, even more preferably 0.8 parts by weight, particularly preferably 0.7 parts by weight, and most preferably 0.6 parts by weight.

[0091] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) and a surfactant (4), the content of the surfactant (4) is, for example, 0.1 to 10 parts by weight per part by weight of the alkali metal or alkaline earth metal halide (3). The lower limit of the content of the surfactant (4) is preferably 0.2 parts by weight, particularly preferably 0.3 parts by weight, and most preferably 0.4 parts by weight. The upper limit of the content of the surfactant (4) is preferably 5 parts by weight, more preferably 3 parts by weight, more preferably 2 parts by weight, even more preferably 1 part by weight, even more preferably 0.8 parts by weight, particularly preferably 0.7 parts by weight, most preferably 0.65 parts by weight, and particularly preferably 0.6 parts by weight.

[0092] The content of surfactant (4) per one pharmaceutical composition (e.g., one capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 15 to 50 mg, preferably 15 to 30 mg.

[0093] (Oil-based base (5)) The oily base (5) is a component that imparts fluidity to the pharmaceutical composition, facilitating formulation (e.g., facilitating filling into capsule shells). The oily base (5) can also improve the dispersibility of nintedanib (1), thereby further improving the dissolution rate of nintedanib (1).

[0094] The oily base (5) is preferably an oily base that is liquid at 25° C. The oily base (5) includes a high-polarity oil and a low-polarity oil, and it is particularly preferable that the oily base (5) contains at least a low-polarity oil. That is, it is particularly preferable that the oily base (5) contains at least a low-polarity oil that is liquid at 25° C.

[0095] An oily base that is liquid at 25° C. is an oily base whose melting point under normal pressure is less than 25° C. The melting point of the oily base is preferably 15° C. or lower, and particularly preferably 10° C. or lower.

[0096] Examples of the low-polarity oils include liquid paraffin, squalane, squalene, tocopherol, tocopherol acetate, tocopherol nicotinate, avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, wheat germ oil, camellia oil, castor oil, safflower oil, cottonseed oil, soybean oil, and peanut oil; and medium-chain triglycerides (MCT).

[0097] The MCT is a compound in which one molecule of glycerol is ester-bonded with three molecules of fatty acid. Examples of the fatty acid include saturated fatty acids having 8 to 12 carbon atoms, such as n-octanoic acid, n-nonanoic acid, n-decanoic acid, and lauric acid.

[0098] Specific examples of the MCT include tricaprylin and tricaprylic acid glyceride.

[0099] Among these, it is preferable that the oily base (5) contains at least MCT.

[0100] In the total amount of the oily base (5), the proportion of MCT is, for example, preferably 50% by weight or more, more preferably 60% by weight or more, even more preferably 70% by weight or more, even more preferably 80% by weight or more, particularly preferably 90% by weight or more, most preferably 95% by weight or more, and particularly preferably 99% by weight or more.

[0101] The oily base (5) may contain an oily base that is solid at 25°C. From the viewpoint of increasing the fluidity of the pharmaceutical composition, the content of the oily base that is solid at 25°C is, for example, preferably 50% by weight or less of the total amount of the oily base (5), more preferably 40% by weight or less, even more preferably 30% by weight or less, even more preferably 20% by weight or less, particularly preferably 10% by weight or less, most preferably 5% by weight or less, and especially preferably 1% by weight or less.

[0102] The content of the oily base that is solid at 25°C is, for example, 35% by weight or less, preferably 30% by weight or less, more preferably 20% by weight or less, even more preferably 10% by weight or less, particularly preferably 5% by weight or less, most preferably 3% by weight or less, and especially preferably 1% by weight or less of the total amount (100% by weight) of the pharmaceutical composition.

[0103] An oily base that is solid at 25°C (an oily base other than an oily base that is liquid at 25°C, including not only solid but also semi-solid oily bases) is an oily base whose melting point under normal pressure is 25°C or higher (e.g., 25 to 50°C).

[0104] The content of the oily base (5) (particularly the oily base that is liquid at 25°C) (the total amount when two or more types are contained) is, for example, 20 to 70% by weight of the total amount of the pharmaceutical composition (100% by weight). The lower limit of the content is preferably 25% by weight, particularly preferably 30% by weight, and most preferably 35% by weight. The upper limit of the content is preferably 60% by weight, particularly preferably 50% by weight, and most preferably 45% by weight.

[0105] When the pharmaceutical composition contains a lipophilic cosurfactant (2) and an alkali metal or alkaline earth metal halide (3), the content of the oily base (5) (particularly, the oily base that is liquid at 25°C) (the total amount when two or more types are contained) is, for example, 20 to 70 wt% of the total amount of the pharmaceutical composition (100 wt%). The lower limit of the content is preferably 25 wt%, particularly preferably 30 wt%, and most preferably 35 wt%. The upper limit of the content is preferably 60 wt%, particularly preferably 50 wt%, most preferably 45 wt%, and particularly preferably 40 wt%.

[0106] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) but does not contain a lipophilic cosurfactant (2), the content of the oily base (5) (particularly, the oily base that is liquid at 25°C) (the total amount when two or more types are contained) is, for example, 20 to 70 wt% of the total amount of the pharmaceutical composition (100 wt%). The lower limit of the content is preferably 25 wt%, particularly preferably 30 wt%, most preferably 35 wt%, and particularly preferably 38 wt%. The upper limit of the content is preferably 60 wt%, particularly preferably 50 wt%, and most preferably 45 wt%.

[0107] The content (total amount when two or more types are contained) of the oily base (5) (particularly, the oily base that is liquid at 25°C) is, for example, 0.5 to 2 parts by weight per part by weight of nintedanib (1). The lower limit of the content of the oily base (5) is preferably 0.6 parts by weight, particularly preferably 0.7 parts by weight. The upper limit of the content of the oily base (5) is preferably 1.8 parts by weight, more preferably 1.7 parts by weight, particularly preferably 1.6 parts by weight, most preferably 1.5 parts by weight, and particularly preferably 1.2 parts by weight.

[0108] When the pharmaceutical composition contains a lipophilic cosurfactant (2) and an alkali metal or alkaline earth metal halide (3), the content (total amount when two or more types are contained) of the oily base (5) (particularly, the oily base that is liquid at 25°C) is, for example, 0.5 to 2 parts by weight per part by weight of nintedanib (1). The lower limit of the content of the oily base (5) is preferably 0.6 parts by weight, particularly preferably 0.7 parts by weight. The upper limit of the content of the oily base (5) is preferably 1.8 parts by weight, more preferably 1.7 parts by weight, even more preferably 1.6 parts by weight, even more preferably 1.5 parts by weight, particularly preferably 1.2 parts by weight, most preferably 1 part by weight, and particularly preferably 0.9 parts by weight.

[0109] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) but does not contain a lipophilic cosurfactant (2), the content (total amount when two or more types are contained) of the oily base (5) (particularly, the oily base that is liquid at 25°C) is, for example, 0.5 to 2 parts by weight per part by weight of nintedanib (1). The lower limit of the content of the oily base (5) is preferably 0.6 parts by weight, particularly preferably 0.7 parts by weight, most preferably 0.8 parts by weight, and particularly preferably 0.9 parts by weight. The upper limit of the content of the oily base (5) is preferably 1.8 parts by weight, more preferably 1.7 parts by weight, particularly preferably 1.6 parts by weight, most preferably 1.5 parts by weight, and particularly preferably 1.2 parts by weight.

[0110] When the pharmaceutical composition contains a lipophilic cosurfactant (2) and an oily base (5), the content of the cosurfactant (2) (total amount when two or more types are contained) is, for example, 5 to 50 parts by weight per 100 parts by weight of the oily base (5). The lower limit of the content of the lipophilic cosurfactant (2) is preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the content of the lipophilic cosurfactant (2) is preferably 40 parts by weight, particularly preferably 35 parts by weight, and most preferably 30 parts by weight.

[0111] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3) and an oily base (5), the content of the alkali metal or alkaline earth metal halide (3) (the total amount when two or more types are contained) is, for example, 5 to 50 parts by weight per 100 parts by weight of the oily base (5). The lower limit of the content of the alkali metal or alkaline earth metal halide (3) is preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the content of the alkali metal or alkaline earth metal halide (3) is preferably 40 parts by weight, particularly preferably 35 parts by weight, and most preferably 30 parts by weight.

[0112] When the pharmaceutical composition contains surfactant (4) and oily base (5), the content of surfactant (4) (total amount when two or more types are contained) is, for example, 5 to 20 parts by weight per 100 parts by weight of oily base (5). The lower limit of the content of surfactant (4) is preferably 7 parts by weight, particularly preferably 10 parts by weight. The upper limit of the content of surfactant (4) is preferably 18 parts by weight, more preferably 16 parts by weight, particularly preferably 15 parts by weight.

[0113] When the pharmaceutical composition contains a lipophilic co-surfactant (2), an alkali metal or alkaline earth metal halide (3), a surfactant (4), and an oily base (5), the content of surfactant (4) (total amount when two or more surfactants are contained) is, for example, 5 to 20 parts by weight per 100 parts by weight of the oily base (5). The lower limit of the content of surfactant (4) is preferably 7 parts by weight, particularly preferably 10 parts by weight, and most preferably 12 parts by weight. The upper limit of the content of surfactant (4) is preferably 18 parts by weight, more preferably 16 parts by weight, and particularly preferably 15 parts by weight.

[0114] When the pharmaceutical composition contains an alkali metal or alkaline earth metal halide (3), a surfactant (4), and an oily base (5), but does not contain a lipophilic co-surfactant (2), the content of surfactant (4) (total amount when two or more surfactants are contained) is, for example, 5 to 20 parts by weight per 100 parts by weight of the oily base (5). The lower limit of the content of surfactant (4) is preferably 7 parts by weight, particularly preferably 10 parts by weight. The upper limit of the content of surfactant (4) is preferably 18 parts by weight, more preferably 16 parts by weight, particularly preferably 15 parts by weight, most preferably 13 parts by weight, and particularly preferably 12 parts by weight.

[0115] The content of the oily base (5) per one pharmaceutical composition (e.g., one capsule or tablet) can be adjusted appropriately depending on the indication, usage, dosage, etc., and is, for example, 100 to 200 mg, preferably 130 to 180 mg.

[0116] (others) The pharmaceutical composition may contain one or more other ingredients in addition to the above ingredients, if necessary.

[0117] Other ingredients include, for example, sweeteners, preservatives, flavoring agents, coloring agents, thickeners, chelating agents, antioxidants, and the like.

[0118] The total content of nintedanib (1), lipophilic cosurfactant (2), alkali metal or alkaline earth metal halide (3), surfactant (4), and oily base (5) accounts for, for example, 50% by weight or more, preferably 60% by weight or more, more preferably 70% by weight or more, even more preferably 80% by weight or more, particularly preferably 90% by weight or more, and most preferably 95% by weight or more of the total content in the pharmaceutical composition. The upper limit of the total content is 100% by weight.

[0119] The dosage form of the pharmaceutical composition is not particularly limited, and examples thereof include soft capsules, hard capsules, tablets, and other pharmaceutical dosage forms.

[0120] (Method of producing pharmaceutical composition) The pharmaceutical composition of the present invention can be produced via a step of mixing nintedanib (1) with a lipophilic co-surfactant (2) and / or an alkali metal or alkaline earth metal halide (3) (hereinafter sometimes referred to as "Step 1").

[0121] Furthermore, when the pharmaceutical composition is a capsule, i.e., when the pharmaceutical composition is a capsule containing a composition comprising nintedanib (1), a lipophilic co-surfactant (2), and / or an alkali metal or alkaline earth metal halide (3), it can be produced by the above-mentioned step 1 and step 2 of filling the composition comprising nintedanib (1), a lipophilic co-surfactant (2), and / or an alkali metal or alkaline earth metal halide (3) obtained through the above-mentioned step 1 into the capsule shell.

[0122] The capsule shell is a container for filling the above ingredients, and may be hard or soft.

[0123] The hard capsule shell is made using a base such as gelatin, hydroxypropylmethylcellulose, etc. The base may also contain a pharmaceutically acceptable coloring agent such as titanium oxide or iron oxide.

[0124] The size of the hard capsule shell is not particularly limited as long as it can contain a therapeutically effective amount of nintedanib (1), and examples include sizes 0 to 5 as specified in the Japanese Pharmacopoeia.

[0125] When the pharmaceutical composition is a hard capsule containing nintedanib (1) and a composition containing a lipophilic cosurfactant (2) and / or an alkali metal or alkaline earth metal halide (3), step 2 is a step of filling the composition into a preformed hard capsule shell. Through steps 1 and 2, a hard capsule can be produced.

[0126] The soft capsule shell is produced using a base material obtained by adding glycerin or sorbitol to gelatin to impart elasticity, for example, and the base material may contain a pharmaceutically acceptable colorant such as titanium oxide or iron oxide.

[0127] When the pharmaceutical composition is a soft capsule encapsulating nintedanib (1) and a composition containing a lipophilic cosurfactant (2) and / or an alkali metal or alkaline earth metal halide (3), step 2 is a step of encapsulating the composition in a soft capsule shell base and sealing it. In step 2, the formation of the capsule shell and the filling of the pharmaceutical composition can be carried out simultaneously. Then, through steps 1 and 2, a soft capsule can be produced.

[0128] Furthermore, when the pharmaceutical composition is a tablet, it can be produced by tableting a composition containing nintedanib (1), a lipophilic co-surfactant (2), and / or an alkali metal or alkaline earth metal halide (3).

[0129] The pharmaceutical compositions (for example, capsules or tablets) produced by the above method may then be packaged in PTP packaging, bottles, aluminum packaging, or the like.

[0130] [Dissolution improver 1] The dissolution improver 1 of the present invention is a compound or composition that improves the dissolution rate of a solid active ingredient (1') in a pharmaceutical composition containing the solid active ingredient (1'), and contains the above-mentioned lipophilic cosurfactant (2).

[0131] In this specification, the solid active ingredient (1') is a compound that is an active ingredient of a pharmaceutical composition, is a compound that is solid at room temperature and normal pressure, and is preferably a hydrophobic compound (with a logD (octanol / water partition coefficient) value at pH 7.4 of, for example, 1 to 5, preferably 2 to 4, and particularly preferably 3). The solid active ingredient (1') includes nintedanib (1) and the like.

[0132] The dissolution improver 1 may contain other components in addition to the lipophilic cosurfactant (2), but the proportion of the lipophilic cosurfactant (2) in the total amount (100% by weight) of the dissolution improver 1 is, for example, 50% by weight or more, preferably 60% by weight or more, more preferably 70% by weight or more, even more preferably 80% by weight or more, particularly preferably 90% by weight or more, most preferably 95% by weight or more, and especially preferably 99% by weight or more, with the upper limit of said proportion being 100% by weight.

[0133] The amount of dissolution improver 1 used is, for example, in the range of 1 to 50 parts by weight of the lipophilic cosurfactant (2) in dissolution improver 1 relative to 100 parts by weight of the solid active ingredient (1') such as nintedanib (1). The lower limit of the amount used is preferably 5 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the amount used is preferably 45 parts by weight, particularly preferably 40 parts by weight, most preferably 35 parts by weight, and particularly preferably 30 parts by weight.

[0134] Addition of the dissolution improver 1 to a pharmaceutical composition containing a solid active ingredient (1') has the effect of improving the dissolution rate of the solid active ingredient (1') in the weakly acidic stomach (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0135] When the dissolution improver 1 is incorporated into a pharmaceutical composition, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, and particularly preferably 70% or more.

[0136] In addition, when a pharmaceutical composition containing nintedanib (1) does not contain dissolution improver 1, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is approximately 40%, and the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is approximately 20%.

[0137] Therefore, the dissolution improver 1 is preferably an agent for improving the dissolution of the solid active ingredient (1') in a weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) aqueous solution.

[0138] [Dissolution improver 2] The dissolution improver 2 of the present invention is a compound or composition that improves the dissolution rate of a solid active ingredient (1') such as nintedanib (1) in a pharmaceutical composition containing the solid active ingredient (1'), and contains an alkali metal or alkaline earth metal halide (3).

[0139] The elution improver 2 may contain other components in addition to the alkali metal or alkaline earth metal halide (3), but the proportion of the alkali metal or alkaline earth metal halide (3) in the total amount (100 wt%) of the elution improver 2 is, for example, 50 wt% or more, preferably 60 wt% or more, more preferably 70 wt% or more, even more preferably 80 wt% or more, particularly preferably 90 wt% or more, most preferably 95 wt% or more, and especially preferably 99 wt% or more, with the upper limit of this proportion being 100 wt%.

[0140] The amount of the dissolution improver 2 used is, for example, in the range of 1 to 50 parts by weight of the alkali metal or alkaline earth metal halide (3) in the dissolution improver 2 relative to 100 parts by weight of the solid active ingredient (1') such as nintedanib (1). The lower limit of the amount used is preferably 5 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the amount used is preferably 45 parts by weight, particularly preferably 40 parts by weight, most preferably 35 parts by weight, and particularly preferably 30 parts by weight.

[0141] When the dissolution improver 2 is added to a pharmaceutical composition containing a solid active ingredient (1'), the dissolution improver 2 penetrates between particles of the solid active ingredient (1') and exerts the effect of suppressing aggregation of the solid active ingredient (1'), thereby improving the dissolution rate of the solid active ingredient (1') in the weakly acidic stomach (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0142] When the dissolution improver 2 is incorporated into the pharmaceutical composition, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, and particularly preferably 70% or more.

[0143] In addition, when the pharmaceutical composition containing nintedanib (1) does not contain dissolution improver 2, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is approximately 40%, and the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is approximately 20%.

[0144] Therefore, the dissolution improver 2 is preferably an agent for improving the dissolution of the solid active ingredient (1') in a weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) aqueous solution.

[0145] [Dissolution improver 3] The dissolution improver 3 of the present invention is a composition that improves the dissolution rate of a solid active ingredient (1') such as nintedanib (1) in a pharmaceutical composition containing the solid active ingredient (1'), and contains the lipophilic co-surfactant (2) and an alkali metal or alkaline earth metal halide (3).

[0146] The weight ratio (former / latter) of the lipophilic cosurfactant (2) to the alkali metal or alkaline earth metal halide (3) in the dissolution improver 3 is, for example, 40 / 60 to 85 / 15. The lower limit of this weight ratio is preferably 45 / 55. The upper limit of this weight ratio is preferably 70 / 30, particularly preferably 60 / 40, and most preferably 55 / 45.

[0147] The dissolution improver 3 may contain other components in addition to the lipophilic cosurfactant (2) and the alkali metal or alkaline earth metal halide (3), but the proportion of the total content of the lipophilic cosurfactant (2) and the alkali metal or alkaline earth metal halide (3) in the total amount (100 wt%) of the dissolution improver 3 is, for example, 50 wt% or more, preferably 60 wt% or more, more preferably 70 wt% or more, even more preferably 80 wt% or more, particularly preferably 90 wt% or more, most preferably 95 wt% or more, and especially preferably 99 wt% or more. The upper limit of this proportion is 100 wt%.

[0148] The amount of the dissolution improver 3 used is, for example, in the range of 5 to 100 parts by weight, where the total amount of the lipophilic cosurfactant (2) and the alkali metal or alkaline earth metal halide (3) in the dissolution improver 3 is 100 parts by weight of the solid active ingredient (1') such as nintedanib (1). The lower limit of the amount used is preferably 10 parts by weight, more preferably 20 parts by weight, particularly preferably 30 parts by weight, most preferably 40 parts by weight, and particularly preferably 50 parts by weight. The upper limit of the amount used is preferably 90 parts by weight, particularly preferably 80 parts by weight, most preferably 70 parts by weight, and particularly preferably 60 parts by weight.

[0149] Addition of the dissolution improver 3 to a pharmaceutical composition containing a solid active ingredient (1') has the effect of improving the dissolution rate of the solid active ingredient (1') in the weakly acidic stomach (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0150] When the dissolution improver 3 is incorporated into the pharmaceutical composition, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, and particularly preferably 70% or more.

[0151] In addition, when the pharmaceutical composition containing nintedanib (1) does not contain dissolution improver 3, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is approximately 40%, and the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is approximately 20%.

[0152] Therefore, the dissolution improver 3 is preferably an agent for improving the dissolution of the solid active ingredient (1') in a weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) aqueous solution.

[0153] [Method 1 for improving dissolution rate] The dissolution rate improving method 1 (or dissolution improving method 1) of the present invention is a method for improving the dissolution rate of a solid active ingredient (1') such as nintedanib (1) by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the solid active ingredient (1').

[0154] The amount of lipophilic cosurfactant (2) used is, for example, in the range of 1 to 50 parts by weight per 100 parts by weight of the solid active ingredient (1'). The lower limit of the amount used is preferably 5 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the amount used is preferably 45 parts by weight, particularly preferably 40 parts by weight, most preferably 35 parts by weight, and particularly preferably 30 parts by weight.

[0155] According to the improvement method, the dissolution rate of the solid active ingredient (1') in a weakly acidic aqueous solution (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) can be improved.

[0156] According to the improved method, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, particularly preferably 70% or more, and most preferably 80% or more.

[0157] Therefore, the improvement method 1 is a method for improving the dissolution rate of the active ingredient in an aqueous solution that is preferably weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0158] [Method 2 for improving dissolution rate] The dissolution rate improving method 2 (or dissolution improving method 2) of the present invention is a method for improving the dissolution rate of a solid active ingredient (1') such as nintedanib (1) by adding an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing the solid active ingredient (1').

[0159] The amount of alkali metal or alkaline earth metal halide (3) used is, for example, in the range of 1 to 50 parts by weight per 100 parts by weight of the solid active ingredient (1'). The lower limit of the amount used is preferably 5 parts by weight, more preferably 10 parts by weight, particularly preferably 15 parts by weight, most preferably 20 parts by weight, and particularly preferably 25 parts by weight. The upper limit of the amount used is preferably 45 parts by weight, particularly preferably 40 parts by weight, most preferably 35 parts by weight, and particularly preferably 30 parts by weight.

[0160] According to the improvement method, the dissolution rate of the solid active ingredient (1') in a weakly acidic aqueous solution (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) can be improved.

[0161] According to the improved method, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, particularly preferably 70% or more, and most preferably 80% or more.

[0162] Therefore, the improvement method 2 is a method for improving the dissolution rate of the active ingredient in an aqueous solution that is preferably weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0163] [Method 3 for improving dissolution rate] The dissolution rate improving method 3 (or dissolution improving method 3) of the present invention is a method for improving the dissolution rate of a solid active ingredient (1') such as nintedanib (1) by adding the lipophilic co-surfactant (2) and an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing the solid active ingredient (1').

[0164] The total amount of the lipophilic cosurfactant (2) and alkali metal or alkaline earth metal halide (3) used is, for example, in the range of 5 to 100 parts by weight per 100 parts by weight of the solid active ingredient (1'). The lower limit of the amount used is preferably 10 parts by weight, more preferably 20 parts by weight, particularly preferably 30 parts by weight, most preferably 40 parts by weight, and particularly preferably 50 parts by weight. The upper limit of the amount used is preferably 90 parts by weight, particularly preferably 80 parts by weight, most preferably 70 parts by weight, and particularly preferably 60 parts by weight.

[0165] The weight ratio (former / latter) of the amount of lipophilic cosurfactant (2) used to the amount of alkali metal or alkaline earth metal halide (3) used is, for example, 40 / 60 to 85 / 15. The lower limit of this weight ratio is preferably 45 / 55. The upper limit of this weight ratio is preferably 70 / 30, particularly preferably 60 / 40, and most preferably 55 / 45.

[0166] According to the improvement method, the dissolution rate of the solid active ingredient (1') in a weakly acidic aqueous solution (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0) can be improved.

[0167] According to the improved method, the dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 1.2 for 1 hour is, for example, 70% or more, preferably 80% or more, and particularly preferably 90% or more. The dissolution rate of nintedanib (1) after immersion in an aqueous solution of pH 3.0 for 1 hour is, for example, 35% or more, preferably 40% or more, more preferably 50% or more, particularly preferably 70% or more, and most preferably 80% or more.

[0168] Therefore, the improvement method 3 is a method for improving the dissolution rate of the active ingredient in an aqueous solution that is preferably weakly acidic (pH, for example, 1.2 to 6.0, preferably 1.2 to 4.0).

[0169] The above-described configurations and combinations of the present invention are merely examples, and the configurations may be added, omitted, substituted, or modified as appropriate without departing from the spirit of the present invention. Furthermore, the present invention is not limited to the embodiments, but is limited only by the claims. [Example]

[0170] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0171] Example 1 58.65 g of medium-chain fatty acid triglyceride (tri(caprylic / capric)glyceryl, trade name "Miglyol 812", manufactured by IOI Oleo GmbH), 8.39 g of polyoxyethylene hydrogenated castor oil (HLB: 14, trade name "HCO-60", manufactured by Nikko Chemicals Co., Ltd.), and PEG 400 (number average molecular weight: 380-420, kinematic viscosity at 98.9°C: 7.1 mm 2 16.758 g of ethanol (trade name "Magcorol 400", manufactured by Maruishi Pharmaceutical Co., Ltd.) was stirred using a homogenizer while heating at 70°C to obtain a mixed solution.

[0172] The resulting mixture (4.356 g) and sodium chloride (0.2302 g) were stirred at 70°C using a homogenizer. Next, 4.154 g of nintedanib ethanesulfonate (D50: 13 μm, log D at pH 7.4: 3.0) was added, and the mixture was stirred at 70°C using a homogenizer to obtain a suspension with the composition (units: parts by weight) shown in Table 1 below.

[0173] 380 mg of the resulting suspension was filled into a hard capsule shell (pork gelatin hard capsule, food grade No. 0, trade name "Licaps Capsule", manufactured by Lonza Co., Ltd.) to obtain a hard capsule.

[0174] Examples 2 to 7 A suspension and hard capsules were obtained in the same manner as in Example 1, except that the blending ratios of PEG400, medium-chain fatty acid triglyceride, and polyoxyethylene hydrogenated castor oil were changed so that the composition of the resulting suspension would be as shown in Table 1 below.

[0175] The hard capsules obtained in the examples were subjected to a dissolution test by the following method. The results are shown in Figure 1. The dissolution rates 30 minutes after the start of the dissolution test are shown in Table 1 below. <Dissolution test method> Using the rotating basket method (100 mesh, 100 rpm) specified in the dissolution test method of the 18th edition of the Japanese Pharmacopoeia, the change in the dissolution rate of nintedanib ethanesulfonate over 180 minutes from the start of the dissolution test was observed using a test solution (37±0.5°C, 900 mL) of pH 3.0 prepared with McIlvaine buffer.

[0176] [Table 1]

[0177] The results of the dissolution rate 30 minutes after the start of the test in Figure 1 and Table 1 show that the pharmaceutical composition of the present invention can ensure the dissolution of nintedanib (1) even under weakly acidic conditions. It can be seen that the dissolution rate of nintedanib (1) under weakly acidic conditions can be significantly improved by adjusting the content of the co-surfactant (2) and the alkali metal or alkaline earth metal halide (3).

[0178] Example 8 A mixture was obtained by stirring 63.60 g of medium-chain fatty acid triglyceride (tri(caprylic / capric)glyceryl, trade name "Miglyol 812", manufactured by IOI Oleo GmbH) and 7.455 g of polyoxyethylene hydrogenated castor oil (HLB: 14, trade name "HCO-60", manufactured by Nikko Chemicals Co., Ltd.) using a homogenizer while heating at 70°C. The resulting mixture (4.669 g) and sodium chloride (1.0672 g) were stirred at 70°C using a homogenizer. Next, 4.154 g of nintedanib ethanesulfonate (D50: 13 μm, log D at pH 7.4: 3.0) was added, and the mixture was stirred at 70°C using a homogenizer to obtain a suspension with the composition (units: parts by weight) shown in Table 2 below. The resulting suspension was filled into hard capsules (size 0) in an amount of 430 mg to obtain hard capsules.

[0179] The obtained hard capsules were subjected to dissolution tests in a pH 3.0 atmosphere and a pH 1.2 atmosphere. The dissolution test in a pH 3.0 atmosphere was performed in the same manner as in Example 1. The dissolution test in a pH 1.2 atmosphere was performed in the same manner as above, except that the pH of the test solution was changed to 1.2. The results are shown in Figures 2 and 3.

[0180] [Table 2]

[0181] In summary, the configuration of the present invention and its variations are described below. [1] The active ingredient (1) is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate, or a pharmaceutically acceptable salt thereof; a lipophilic co-surfactant (2); A pharmaceutical composition comprising: [2] The lipophilic co-surfactant (2) is represented by the following formula (2a): HO-(R 1 -O) n -H (2a) (In the formula, R 1 represents an alkylene group which may have a substituent, and n represents an integer of 1 or more. The pharmaceutical composition according to [1], wherein the (poly)alkylene polyol is represented by the following formula: [3] The pharmaceutical composition according to [1] or [2], wherein the lipophilic co-surfactant (2) has a number average molecular weight of 100 to 1,000. [4] The lipophilic cosurfactant (2) has a kinematic viscosity at 98.9°C of 1 to 15 mm 2 The pharmaceutical composition according to any one of [1] to [3], wherein: [5] The pharmaceutical composition according to any one of [1] to [4], wherein the lipophilic co-surfactant (2) is polyethylene glycol. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the content of the lipophilic co-surfactant (2) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1). [7] The pharmaceutical composition according to any one of [1] to [6], further comprising an alkali metal or alkaline earth metal halide (3). [8] The pharmaceutical composition according to [7], wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide. [9] The pharmaceutical composition according to [7] or [8], wherein the weight ratio (former / latter) of the lipophilic cosurfactant (2) to the alkali metal or alkaline earth metal halide (3) is 40 / 60 to 85 / 15.

[10] The pharmaceutical composition according to any one of [7] to [9], wherein the content of the alkali metal or alkaline earth metal halide (3) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1).

[11] The pharmaceutical composition according to any one of [1] to

[10] , further comprising at least one surfactant (4) selected from polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, and (poly)glycerin fatty acid ester.

[12] The pharmaceutical composition according to any one of [1] to

[11] , further comprising an oily base (5).

[13] The pharmaceutical composition according to

[12] , wherein the content of the oily base (5) is 0.5 to 2 parts by weight per 1 part by weight of the active ingredient (1).

[14] The pharmaceutical composition according to any one of [1] to

[13] , which is in the form of a capsule or a tablet.

[15] A method for producing a pharmaceutical composition, comprising the step of mixing the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with a lipophilic co-surfactant (2), to obtain the pharmaceutical composition according to any one of [1] to

[14] .

[16] A dissolution improver for improving the dissolution rate of the active ingredient (1) in a pharmaceutical composition comprising methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, the active ingredient (1), A dissolution improver containing a lipophilic co-surfactant (2).

[17] A method for improving the dissolution of an active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof (1), by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the active ingredient (1).

[18] A dissolution improver for improving the dissolution rate of a solid active ingredient (1') in a pharmaceutical composition containing the active ingredient (1'), comprising: A dissolution improver containing a lipophilic co-surfactant (2).

[19] A method for improving the dissolution of a solid active ingredient (1') by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the active ingredient (1').

[20] The active ingredient (1) is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof; an alkali metal or alkaline earth metal halide (3); A pharmaceutical composition comprising:

[21] The pharmaceutical composition according to

[20] , wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide.

[22] A method for producing a pharmaceutical composition according to

[20] or

[21] , comprising the step of mixing the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with an alkali metal or alkaline earth metal halide (3).

[23] A dissolution improver for improving the dissolution rate of the active ingredient (1) in a pharmaceutical composition containing methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, the active ingredient (1), A dissolution improver containing an alkali metal or alkaline earth metal halide (3).

[24] A method for improving the dissolution of an active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, by adding an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing the active ingredient (1).

[25] A dissolution improver for improving the dissolution rate of a solid active ingredient (1') in a pharmaceutical composition containing the active ingredient (1'), the dissolution improver comprising an alkali metal or alkaline earth metal halide (3).

[26] A method for improving dissolution rate by adding an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing a solid active ingredient (1').

Claims

1. an active ingredient (1) methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof; a lipophilic co-surfactant (2); 10. A pharmaceutical composition comprising:

2. The lipophilic co-surfactant (2) is represented by the following formula (2a): HO-(R 1 -O) n -H (2a) (In the formula, R 1 represents an alkylene group which may have a substituent, and n represents an integer of 1 or more. The pharmaceutical composition according to claim 1, wherein the (poly)alkylene polyol is represented by the formula:

3. 3. The pharmaceutical composition according to claim 1, wherein the lipophilic co-surfactant (2) has a number average molecular weight of 100 to 1,000.

4. The kinematic viscosity of the lipophilic cosurfactant (2) at 98.9°C is 1 to 15 mm 2 The pharmaceutical composition according to claim 1 or 2, wherein the formula is / s.

5. 3. The pharmaceutical composition according to claim 1, wherein the lipophilic co-surfactant (2) is polyethylene glycol.

6. 3. The pharmaceutical composition according to claim 1, wherein the content of the lipophilic co-surfactant (2) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1).

7. The pharmaceutical composition according to claim 1 or 2, further comprising an alkali metal or alkaline earth metal halide (3).

8. The pharmaceutical composition according to claim 7, wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide.

9. 8. The pharmaceutical composition according to claim 7, wherein the weight ratio (former / latter) of the lipophilic co-surfactant (2) to the alkali metal or alkaline earth metal halide (3) is 40 / 60 to 85 / 15.

10. 8. The pharmaceutical composition according to claim 7, wherein the content of the alkali metal or alkaline earth metal halide (3) is 3 to 50 parts by weight per 100 parts by weight of the active ingredient (1).

11. The pharmaceutical composition according to claim 1 or 2, further comprising at least one surfactant (4) selected from polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, and (poly)glycerin fatty acid ester.

12. The pharmaceutical composition according to claim 1 or 2, further comprising an oily base (5).

13. The pharmaceutical composition according to claim 12, wherein the content of the oily base (5) is 0.5 to 2 parts by weight per 1 part by weight of the active ingredient (1).

14. 3. The pharmaceutical composition according to claim 1, which is in the form of a capsule or a tablet.

15. 3. A method for producing a pharmaceutical composition according to claim 1 or 2, comprising the step of mixing an active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with a lipophilic co-surfactant (2).

16. A dissolution improver for improving the dissolution rate of an active ingredient (1) in a pharmaceutical composition comprising the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, A dissolution improver containing a lipophilic co-surfactant (2).

17. A method for improving the dissolution of an active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof (1), by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the active ingredient (1).

18. A dissolution improver for improving the dissolution rate of a solid active ingredient (1') in a pharmaceutical composition containing the active ingredient (1'), A dissolution improver containing a lipophilic co-surfactant (2).

19. A method for improving the dissolution of a solid active ingredient (1') by adding a lipophilic co-surfactant (2) to a pharmaceutical composition containing the active ingredient (1').

20. an active ingredient (1) which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof; an alkali metal or alkaline earth metal halide (3); 10. A pharmaceutical composition comprising:

21. 21. The pharmaceutical composition of claim 20, wherein the alkali metal or alkaline earth metal halide (3) is at least one compound selected from sodium chloride, potassium chloride, and sodium iodide.

22. 21. A method for producing a pharmaceutical composition according to claim 20, comprising the step of mixing an active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, with an alkali metal or alkaline earth metal halide (3).

23. A dissolution improver for improving the dissolution rate of an active ingredient (1) in a pharmaceutical composition comprising the active ingredient (1), methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, A dissolution improver containing an alkali metal or alkaline earth metal halide (3).

24. A method for improving the dissolution of an active ingredient (1), which is methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate or a pharmaceutically acceptable salt thereof, by incorporating an alkali metal or alkaline earth metal halide (3) into a pharmaceutical composition containing the active ingredient (1).

25. A dissolution improver for improving the dissolution rate of a solid active ingredient (1') in a pharmaceutical composition containing the active ingredient (1'), the dissolution improver comprising an alkali metal or alkaline earth metal halide (3).

26. A method for improving the dissolution rate by adding an alkali metal or alkaline earth metal halide (3) to a pharmaceutical composition containing a solid active ingredient (1').

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